Development of a percutaneous delivery system based on a natural biopolymer is proposed for the reduction of irritation caused by the chronic topical delivery of all-trans-retinoic acid (ATRA). A national Phase II trial led by the Eastern Cooperative Oncology Group is now investigating the effects of topical ATRA for the chemoprevention of melanoma. Preliminary studies using Franz diffusion cells have shown that the natural biopolymer significantly reduces the amount of retinoid delivery across the skin, thus reducing systemic overload. In this Phase I feasibility study we propose: (1) to examine the role of the natural biopolymer for the controlled percutaneous delivery of both conventional and radiolabeled ATRA by determining the penetration and distribution of retinoid across hairless mouse skin as a function of retinoid dose, biopolymer content and molecular weight; and (2) to establish the tolerance of topical applications of biopolymer-based and control ATRA gels of three different strengths as evaluated by human patch testing. The long-term goal of the proposed application is to develop natural biopolymer-based percutaneous delivery system for the chemoprevention of melanoma in individuals with dysplastic nevi who are at risk of developing melanoma. PROPOSED COMMERCIAL APPLICATION: A controlled topical delivery system could make ATRA retinoid therapy a viable chemopreventive treatment of melanoma, which is the fastest rising cancer in the United States. The use of a natural biodegradable biopolymer with proven safety track record in cosmetic products is expected to provide a better alternative to the current use of synthetic polymers for the topical delivery of ATRA.